Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

Bryant, Jean-Paul; Heiss, John D.; Banasavadi-Siddegowda, Yeshavanth

doi:10.3390/cells10010124

Cited by 16 publications

(12 citation statements)

References 140 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PRMT inhibitors have been hailed as novel, promising drugs for the treatment of several cancer types. This is based on remarkable success in the synthesis of specific inhibitors and on encouraging preclinical and clinical models of disease, ,− which have led to clinical trials by major pharmaceutical companies. The research community has appreciated the need to monitor any side-effects of these emerging class of drugs, and our work raises the need to consider platelet inhibition as a possible off-target effect of the systemic administration of PRMT inhibitors in ongoing and subsequent clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Arginine Methylation Impairs Platelet Function

Marsden

Riley

Barry

et al. 2021

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

Protein arginine methyltransferases (PRMTs) catalyse the transfer of methyl groups to arginine residues in proteins. PRMT inhibitors are novel, promising drugs against cancer that are currently in clinical trials, which include oral administration of the drugs. However, off-target activities of systemically available PRMT inhibitorshave not yet been investigated. In this work, we study the relevance of arginine methylation in platelets and investigate the effect of PRMT inhibitors on platelet function and on the expression of relevant platelet receptors.We show that (1) key platelet proteins are modified by arginine methylation, (2) incubation of human platelets with PRMT inhibitors for 4 hours results in impaired capacity of platelets to aggregate in response to thrombin and collagen, with IC50 values in the µM range, and (3) treatment with PRMT inhibitors leads to decreased membrane expression and reduced activation of the critical platelet integrin αIIbβ3. Our contribution opens new avenues for research on arginine methylation in platelets, including the repurposing of arginine methylation inhibitors as novel antiplatelet drugs. We also recommend that current and future clinical trials with PRMT inhibitors consider any adverse effects associated with platelet inhibition of these emerging anti-cancer drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of Arginine Methylation Impairs Platelet Function

Marsden

Riley

Barry

et al. 2021

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

show abstract

“…Protein arginine methyltransferases (PRMTs) are critical enzymes responsible for adding methyl groups onto arginine residues within target proteins. Emerging evidence within the last decade suggests a strong nexus between aberrancies in PRMTs function and GBM tumorigenesis [ 106 , 107 ]. Hence, PRMT inhibitors are currently under development for preclinical and clinical trials in GBM patients.…”

Section: Targeting Epigenetic Alterationmentioning

confidence: 99%

The Impact of Epigenetic Modifications on Adaptive Resistance Evolution in Glioblastoma

Berglund

Etame

2021

IJMS

View full text Add to dashboard Cite

Glioblastoma (GBM) is a highly lethal cancer that is universally refractory to the standard multimodal therapies of surgical resection, radiation, and chemotherapy treatment. Temozolomide (TMZ) is currently the best chemotherapy agent for GBM, but the durability of response is epigenetically dependent and often short-lived secondary to tumor resistance. Therapies that can provide synergy to chemoradiation are desperately needed in GBM. There is accumulating evidence that adaptive resistance evolution in GBM is facilitated through treatment-induced epigenetic modifications. Epigenetic alterations of DNA methylation, histone modifications, and chromatin remodeling have all been implicated as mechanisms that enhance accessibility for transcriptional activation of genes that play critical roles in GBM resistance and lethality. Hence, understanding and targeting epigenetic modifications associated with GBM resistance is of utmost priority. In this review, we summarize the latest updates on the impact of epigenetic modifications on adaptive resistance evolution in GBM to therapy.

show abstract

“…Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is an abundant post-translational modification involved in various essential cellular processes. Emerging evidence has linked alterations in PRMTs to a variety of cancers, including brain tumors [ 1 ]. Thus, PRMTs may represent attractive targets for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…PRMT1 and PRMT5 are the predominant type I and II PRMTs that catalyze most asymmetrical di-methylarginine and symmetrical di-methylarginine marks, respectively. PRMT5 was the first PRMT to be targeted in clinical trials for brain tumors [ 1 ]. A recent report identified PRMT5 as a critical regulator of expression of MYC, an oncoprotein that drives the pathogenesis of MYC -amplified Group 3 medulloblastomas [ 3 ].…”

Section: Introductionmentioning

confidence: 99%